Clinical Observation of a Novel, Complementary ... · Original Research Paper Clinical Observation of a Novel, Complementary, Immunotherapeutic Approach based on Ketogenic Diet, Chondroitin
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Immunotherapy of cancer has gained a great deal of
attention in recent years up to the point that the Editors
of the journal “Science” have chosen cancer
immunotherapy as “Breakthrough of the Year for 2013”
defining this as “a strategy that harnesses the body's
immune system to combat tumors” (Science. 2013 Dec
20; 342 (6165): 1432-3). Although the term
“immunotherapy” encompasses several strategies that
may significantly differ from each other, the common
denominator is to target the immune system rather than
the tumor itself. This approach is based on the rationale
that cancer cells are able to escape immune surveillance
because of the typically immunosuppressive tumor
microenvironment (Mohme et al., 2016) and, in doing
so, they take advantage of the unresolved chronic
inflammation that is present in all stages of cancer
development. Thus, inflammation at the level of the
tumor microenvironment and at the systemic level as
cancer progresses, is one of the ubiquitous features of
cancer (Pesic and Greten, 2016).
Because of this, among the different approaches to
the immunotherapy of cancer, those strategies based on
ad-hoc formulated nutritional plans and on food
supplements that stimulate the immune system and fight
inflammation appear to be most promising. Thus, these
approaches are characterized by inherent low toxicity
and by the possibility to use them in conjunction with
conventional anti-cancer therapies targeting cancer cells
such as radiation or chemotherapies.
In this clinical case report, we describe the effects of
a novel type of complementary immunotherapy of cancer
that is based on a combination of ketogenic diet,
administration of an emulsion made of chondroitin
sulfate, vitamin D3 and oleic acid and of a fermented
milk and colostrum product. The role of ketogenic diets in cancer has been known
for decades and there exists strong evidence supporting
the concept that ketogenic diets may be safely used as
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adjuvant therapies in conjunction with conventional
radiation and chemotherapies (Allen et al., 2014).
Although the historical rationale to implement ketogenic
diets in cancer was to deprive cancer cells of their main
source of energy, glucose, diets that are characterized by
very low carbohydrate consumption show other
properties that are useful in the integrated management
of cancer. Thus, they reduce the synthesis de novo of a
second messenger deriving from glycolysis,
diacylglycerol, that is responsible for increased
resistance to the killing effects of ionizing radiations
(Chiarugi et al., 1989; Ruggiero et al., 1992). It can be
hypothesized that decreased synthesis of diacylglycerol
may be responsible for the increased sensitivity to the
therapeutic effects of radiation therapy that has been
observed with the implementation of ketogenic diets
(Klement and Champ, 2014). In addition, it has been
recently demonstrated that ketone bodies have anti-
inflammatory, pro-immunogenic properties that are quite
relevant in the context of an integrated
immunotherapeutic approach to cancer and other
diseases associated with chronic inflammation and
immunodeficiency (Youm et al., 2015).
In this study we describe clinical cases where the
ketogenic diet was integrated with supplements aimed at
stimulating the immune system at the same time
decreasing inflammation. To this end, we used an
emulsion composed of supplements endowed with
immune-stimulatory, anti-cancer and anti-inflammatory
properties. These supplements are chondroitin sulfate,
vitamin D3 and oleic acid.
The rationale for choosing chondroitin sulfate lays in the observation that this glycosaminoglycan is known to negatively regulate cancer cell signaling (Willis and Klüppel, 2014) and to enhance the anti-tumor activity of conventional chemotherapeutics (Ferro et al., 2012). Recent experimental evidence demonstrated that sulfated motifs of chondroitin sulfate are also able to inhibit triple negative breast cancer (Poh et al., 2015). In addition, chondroitin sulfate is a powerful anti-inflammatory agent (Vallières and du Souich, 2010) with known immune-stimulating properties. Thus, chondroitin sulfate stimulates macrophages with the resulting production of nitric oxide, a molecule known to kill cancer cells (Sharma and Chakrapani, 2014), without inducing the production of pro-inflammatory cytokines (Wrenshall et al., 1999).
Vitamin D3 was chosen for two main reasons: one is
that a known side effect of ketogenic diets is vitamin D3
deficiency, an occurrence that was first observed in
children subjected to such a diet to control epilepsy
(Hahn et al., 1979; Bergqvist et al., 2007). The other
reason is that vitamin D3 is known to have anti-cancer
and anti-inflammatory properties (Ness et al., 2015).
Thus, vitamin D3 regulates the cell cycle, induces
apoptosis of cancer cells, promotes cell differentiation
and works as a natural anti-inflammatory agent within
the tumor microenvironment (Díaz et al., 2015).
The rationale for choosing oleic acid, that is the most
represented fatty acid of olive oil, lays in the century old
observation that olive oil is a powerful anti-cancer agent
up to the point that a recent article poses the rhetorical
(Colomer et al., 2008). In addition, mono- and poly-
unsaturated fatty acids such as oleic acid significantly
decrease the affinity of vitamin D3 for the its binding
protein, thus increasing the bioavailability of vitamin D3
(Bouillon et al., 1992).
Therefore, the concomitant presence of oleic acid and
vitamin D3 in an emulsion also containing chondroitin
sulfate may show overall synergistic effects that may be
higher than the sum of the anti-cancer and anti-
inflammatory properties of each individual component
taken singularly.
Finally, the rationale to use a fermented milk and
colostrum product lays in the observation that such
products are known to enhance the immune system,
reduce the risk of certain cancers and decrease systemic
inflammation thus synergizing with the effects of the
ketogenic diet and of the emulsion of chondroitin sulfate,
vitamin D3 and oleic acid quoted above (Khani et al.,
2012; Falasca et al., 2015).
Patients and Methods
Methodological Approach
The nutritional-immunotherapeutic approach
described in the Introduction is currently implemented in
a number of Clinics, mainly in Europe and it is tailored
to the individual situation of each patient. Here we
present four cases observed in Germany by Drs.
Schwalb, M.D. and Taubmann, N.D. A fifth case, patient
5, was reported to Dr. Reinwald. A sixth case, patient 6,
was observed by Dr. Hines, N.D., N.E.
It is important to notice that the approaches aimed at
strengthening the immune system have to be considered
complementary and not alternative to other anti-cancer
therapeutic procedures.
We are very well aware that the cases reported here
have to be considered anecdotal because of their
heterogeneity and small number. It is worth noticing,
however, that a study on the evaluation of clinical
practice re-evaluates the importance of individual cases
in determining the effectiveness of clinical procedures
(Nunn, 2011) and, according to Cox, cases such as those
reported here “expand expertise, are the unit of clinical
work, provide a frame-work for complex details and
explain decisions” (Cox, 2001). We chose to report
single cases rather than statistics following the indication
of Aronson, according to whom the description of single
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cases generates and tests hypotheses, elucidate
mechanisms and remind or educate (Aronson, 2005).
Patients were treated in compliance with national
rules and regulations. Ultrasound determinations,
whenever possible, were performed by the Therapists
treating the patients. Blood analyses were performed by
European certified laboratories. Determination of serum
α-N-acetylgalactosaminidase, an enzyme also known as
Nagalase, was performed by the European Laboratory of
Nutrients (The Netherlands). The original clinical
records are conserved in the offices of the Therapists.
Descriptions of the clinical cases are reported as close as
possible to the originals notes of the Therapists, with
minimal grammar and spelling corrections for the sake
of clarity and consistency throughout the text.
Nutritional Approach
Patients were invited to follow a diet very low in
carbohydrates and rich in fats endowed with anti-
inflammatory properties such as extra-virgin olive oil
and coconut oil. Since most patients presented with
advanced cancer and were at risk of entering the
cachexia-anorexia syndrome, their diet was
supplemented with a specific amino acid formula which
provides an anabolic value close to 99% and, therefore,
releases less than 1% of nitrogen waste (ammonia) or
energy compared to, for example, formulas containing
whey or soy proteins which provide only 16-17%
anabolic building blocks and release up to 84% of
nitrogen waste and energy (mostly glucose) while being
catabolized. As the amino acids in the special formula
do not need peptidases to be digested they could be used
also in patients with pancreatic cancer to prevent
cachexia. The formula was manufactured by the
company “dr. reinwald healthcare” (Germany).
The fermented milk and colostrum product consumed
by the patients described in this study was produced in
Switzerland by the company “Silver Spring”; the
immune-stimulating properties of this particular
formulation have been described elsewhere (Pacini et al.,
2011). The typical daily dose was about 120 mL.
Under the responsibility of the Therapists, this
fermented milk product was also administered under the
form of enema. Thus, it is well known that probiotics
administered by enemas reduce the inflammatory status
in experimental colitis (Souza et al., 2007) and rectal
administration of lactobacilli in children with active
distal ulcerative colitis effective in reducing mucosal
inflammation and changing mucosal expression levels
of cytokines involved in the mechanisms of
inflammatory bowel disease (Oliva et al., 2011). In
addition, it has been recently demonstrated that the off-
label use of milk and molasses enemas is safe and
effective in treating constipation with negligible side
effects (Vilke at al., 2015).
Supplements
All the patients described in this report were
administered the emulsion of chondroitin sulfate,
vitamin D3 and oleic acid quoted in the Introduction.
Such an emulsion is manufactured in Germany by “dr.
reinwald healthcare” and it is classified and registered as
a food supplement since it is composed by well-known
supplements that have been in use for decades. Although
supplements are usually intended to be administered
through the oral route, according to national rules and
regulations and under the direct responsibility of the
Therapist, they can also be administered through the
parenteral route. Thus, the emulsion quoted above was
administered orally or parenterally according to the
clinical judgment of the Therapist in each individual case.
Other supplements used in the patients described in
this study were: Vitamin D3 (10.000-20.000 I.U. per
day), curcumin, omega-3, ubiquinol, arginine,
multivitamins and a low-molecular weight pectin
preparation. This latter product was provided for by
“dr. reinwald healthcare” whereas all the other
supplements were obtained from local pharmacies and
supplement stores. The rationale for the use of low-
molecular weight pectin lays in the observation that
pectin effectively inhibits the growth and metastasis of
gastrointestinal cancer cells (Wang et al., 2016). In
addition, pectin is effective at removing toxicants; a
study published in 2008, demonstrated that oral
administration of pectin was effective at lowering lead
toxicity in the blood of children who showed a dramatic
decrease in blood serum levels of lead and a dramatic
increase in 24 h urine collection with no observed
adverse effects (Zhao et al., 2008).
Finally, it should be noticed that each patient
followed specific therapeutic regimens consistent with
their co-morbidities such as, for example, hypertension
or hypothyroidism.
Results
Patient 1
A 70-year old lady was diagnosed with ovarian cancer with multiple metastases in the liver and the peritoneum. Before coming to the attention of the Therapist, she had been treated with multiple cycles of conventional chemotherapy that resulted in reduction of the size of the peritoneal metastases, but were ineffective against the hepatic metastases. The patient had developed severe neuropathy possibly as a consequence of chemotherapy and she could not walk for more than ten meters due to extreme pain and fatigue. The patient had been labeled “incurable” and she had been advised to prepare for the inevitable outcome. The patient came to the attention of the Therapist in such a depressing context and she was treated with the nutritional-
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immunotherapeutic approach described in the preceding sections; after about five weeks of treatment, a Positron Emission Tomography (PET) scan did not evidence any appreciable liver metastasis. Blood analyses evidenced elevated percentage of circulating monocytes (8.1%. Normal values: 3-10%), thus supporting the hypothesis that the integrated approach described above stimulated the immune system with particular reference to the monocyte-macrophage arm of immunity. Activation of macrophages following the subcutaneous administration of the emulsion described above was also confirmed by color-doppler ultrasonography following the technique that one of us had described in 2014 (Ruggiero et al., 2014). Most interesting was the decrease of Transketolase-Like 1 (TKTL1) score. Thus, TKTL1 plays a crucial role in ovarian cancer metabolism and its expression predicts poor prognosis (Krockenberger et al., 2010); therefore, decrease in the expression of TKTL1 may be interpreted as sign of decreased aggressiveness of the cancer itself. It should be noticed, however, that TKTL1 expression is not unique for ovarian cancers and it appears that TKTL1 belongs to a group of metabolic genes involved in the glycolytic pathway that is significantly up-regulated in a variety of tumor cells in cancer patients and plays active roles in tumor progression (Furuta et al., 2010). The cumulative TKTL1 score after five weeks of treatment was 125 that is very close to normal values (normal value: less than 119). Also the Apo10 score was decreased, thus confirming the effectiveness of the immunotherapeutic approach from another point of view. Thus, Apo10 is a marker of abnormal apoptosis and proliferation and it represents an independent marker for poor survival for certain carcinomas (Grimm et al., 2013). Consistent with these observations, it has been recently proposed that overcoming drug resistance of Apo10-positive cells in precursor lesions and tumors by natural compounds may act as sensitizers for apoptosis or could be useful for chemoprevention (Grimm et al., 2015). The cumulative Apo10 score after treatment was 149 (normal value: less than 130).
Patient 2
A 63-year old man was diagnosed with prostate
adenocarcinoma, osteoporosis and esophagitis. The
patient had previously been treated with radiation
therapy. Magnetic Resonance Imaging (MRI) showed
residual tumor lesion. After about four weeks of
treatment with the nutritional-immunotherapeutic
approach described in the previous sections, Prostate-
Specific Antigen (PSA) was significantly decreased from
95 to 0.8 ng mL−1
, i.e., the tumor marker had returned to
normal values. It is worth noticing that while this patient
was undergoing the approach described above, he also
received for three times subcutaneous anti-androgen
treatment from the Department of Urology of the
University of Bochum, Germany. Interestingly, the
dramatic drop of PSA from 95 to 0.8 ng mL−1
occurred
after the first administration of anti-androgens; the
patient refers that such an abrupt decrease puzzled the
Oncologists who were treating him since, according to
the patient’s story, this was the first time that they had
observed such an occurrence. Imaging studies showed
significant reduction of the tumor mass that appeared
encapsulated with no metabolic activity. The
percentage of circulating monocytes was close to the
highest normal values (9.2%. Normal value: 3-10%)
and activation of macrophages following subcutaneous
administration of the emulsion described above was
confirmed by color-doppler ultrasonography.
Cumulative TKTL1 and Apo10 scores were decreased
and, at the end of the treatment, both scores where within
the normal values (TKTL1: 115. Apo10: 112).
Patient 3
A 66-year old lady was diagnosed with mammary
adenocarcinoma, cholelithiasis, colitis and atrial
fibrillation. At the time of presentation the tumor
measured 0.4 cubic centimeters in volume. Bearing in
mind that measurements taken on ultrasonographic images
may be affected by a number of variables, preliminary
evidence appears to indicate that, three weeks after
implementation of the nutritional-immunotherapeutic
approach described above, the tumor measured 0.1 cubic
centimeters with a reduction of 75% of volume. Also in
this case the Therapists observed normalization of the
cumulative Apo10 score (value: 123) that was consistent
with the observed reduction in tumor size.
Patient 4
A 55-year old man was diagnosed with recurrences
of adenocarcinoma and adenosarcoma of the esophagus
with lung metastases; such recurrences had occurred
after a previous surgical intervention targeting these
lesions. Also in this case, the patient had been labeled
“incurable”. After about eight months of implementation
of the nutritional-immunotherapeutic treatment described
above, the local lesions appear stable and encapsulated
with no signs of progression. A Computed Tomography
(CT) scan of the thorax performed after about eight
months, did not show lesions as if the metastases were no
longer detectable. The general conditions of the patients
were significantly improved up to the point that the
Percutaneous Endoscopic Gastrostomy (PEG) tube was
removed as no longer necessary. The patient reported that
the Specialists at the University of Dusseldorf, Germany,
where these latter procedures were performed, were
utterly puzzled by the unexpected positive outcome. Thus,
it is well known that the prognosis for esophagus cancer is
quite poor with most patients dying within the first year of
diagnosis (Polednak, 2003).
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Patient 5
A 59-year old man was diagnosed one year earlier
with pulmonary nodule of unknown origin. The patient
was recommended to undergo surgical excision of the
nodule but he preferred to decline such a
recommendation and he opted for a multitude of
nutritional-complementary approaches which included,
among others, low-dose naltrexone, coffee enemas,
quercetin, multivitamins, oregano oil, minerals. The
patient assumed specific drugs for the following co-
morbidities; hypertension, left ventricular hypertrophy,
hypothyroidism. Tumor markers such as
Carcinoembryonic Antigen (CEA), Prostate Specific
Antigen (PSA), CA 19-9, CA 27-29 and CA 15-3 were
within the normal limits. An interesting laboratory
abnormality was represented by level of the serum
enzyme Nagalase that was significantly elevated when the
patient decided to implement the nutritional-
immunotherapeutic approach described in this study.
Thus, determination of serum Nagalase resulted in 3.10
Units (expressed as nmol/min/mg) that was well above the
indicated reference range of 0.32-0.95 Units. It is
interesting to notice that Nagalase may represent at the
same time a tumor marker, a marker of inflammation and a
marker of bacterial infection. Thus, Taniguchi et al. (1981)
demonstrated that squamous cell carcinomas showed
increased expression of this enzyme (Taniguchi et al.,
1981), whereas Caines et al. (2008) demonstrated that
the enzyme is an important virulence factor for
Streptococcus Pneumoniae infections (Caines et al.,
2008). The patient repeated Nagalase determination
about six months after having implemented the approach
described above and the results, from the same European
laboratory, showed a very significant decrease of the
enzyme that approached the normal values (1.34 Units).
These results seem to indicate that the
immunotherapeutic approach adopted by the patient was
effective in decreasing the level of serum Nagalase in a
manner consistent with what previously reported for
other types of cancer (Thyer et al., 2013).
Patient 5
A fortuitous misunderstanding. Report by Dr. Hines.
“In April 2016, we had an interesting situation occur at
our treatment facility. A woman, age 73, came to us
suffering with epigastric pain, nausea, vomiting and
pitting edema in both feet. Her diagnosis was
cholangiocarcinoma. Her oncologist stated she was not a
candidate for surgery and did not offer any treatment or
hope for recovery. The tumor measured 5×6.5 cm,
involving the common bile duct. We recommended the
patient order 3 vials of the emulsion of chondroitin sulfate,
vitamin D3 and oleic acid quoted in the Introduction. She
was instructed to take 0.5 cc once daily for 5 days, then
take 2 days off. One week later, she returned to our clinic
for her scheduled intravenous treatments. When she
arrived, I asked her about her epigastric pain, nausea,
vomiting and pitting edema. Her answer: No pain, no
nausea, no vomiting and only a minor edema in the feet.
I was quite surprised at this. When I asked her how
much product she was taking, she said she had finished
all 3 vials the previous week. The 3 ampoules she had
should have lasted for at least a few months, but she
had already taken them all in one week! She had
misunderstood my dosing recommendations and had
taken 1 ampoule daily for 3 days in a row sublingually.
Heroic doses to say the least. Now, 6 months later, she
still feels just fine and is living a normal life.”
Discussion
The efficacy of chondroitin sulfate and vitamin D3 in
cancer is acknowledged not only by the scientific
literature quoted in the Introduction but also by the
prestigious Mayo Clinic of the United States of America
in the section where clinical evidences for different
supplements are reported. In the list of the uses for
chondroitin sulfate based on tradition or scientific theories
listed by the Mayo Clinic, the following uses in cancer can
be found: “breast cancer, colorectal cancer, lung cancer,
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